11/5/2014
Fluid Overload: Are We Drowning
Our Patients?
Amanda Hassinger, MD
Attending Physician, Pediatric Critical Care
WCHOB Pediatric Grand Rounds
November 7, 2014
“I at length resolved to throw the fluid immediately
into the circulation… Having inserted a tube into
the basilic vein, cautiously - anxiously, I watched
the effects; ounce after ounce was injected… I
thought she began to breathe less laboriously, soon
the sharpened features, and sunken eye, and fallen
jaw, pale and cold, bearing the manifest impress of
death’s signet, began to glow with returning
animation; the pulse which had long ceased, returned
to the wrist;… and in the short space of half an
hour, when six pints had been injected, she
expressed in a firm voice that she was free from all
uneasiness, actually became jocular, and fancied all
she needed was a little sleep.”
Latta T. The Lancet (1832); 18(468):640.
Disclosures
Intravenous fluids: a new therapy
• No stock in Lasix
• No personal vendettas against IVF
Indication:
Correct hypovolemia from excessive losses:
a) Dehydration from diarrhea or vomiting
b) Excessive loss from exercise or heat with impaired
thirst.
Bladder syringe, 1900’s
Objectives
• The foundations of intravenous fluid therapy
• Functions:
– Dr. Thomas Latta, 1832
– Holliday and Segar, 1957
• Discuss our understanding of “hydration”
– Macrovascular: Frank-Starling
Ernest Henry Starling
(1866-1927)
• Evidence of the benefits of IV fluids
• Evidence of the association between FO and worse outcomes
– Microvascular: Starling, again!
– ESL
– Tissue perfusion
• The new paradigm for fluid management
*WARNING: no CRRT, diuretics or types of IVF will be discussed.*
– Solvent for ionic compounds and solutes like amino acids,
glucose
– Essential to all hydrolytic reactions
– The medium in which all transport systems function: between
cells, interstitial fluid and capillaries
– Maintains intravascular volume to allow circulation of blood
components
– Uses its large heat capacity to maintain thermoregulation in
extremes of ambient temperatures
• 2.2kJ of heat is lost by evaporation of 1gm of water
– Shock absorber for joints, the brain, the fetus while in utero
– Forms lubricating fluids for the mouth, GI tract, respiratory
system and the GU tract
1
11/5/2014
The science of hydration
Neonates
and infants
↓ICF
Neonates and
infants
↑ECF
10 kg child →
7L TBW →
3.5L ECF →
700 mL
plasma
= 70ml/kg
• 60%* of our body weight is made up of H2O
– Approx 2/3 is intracellular
– Approx 1/3 is retained in the extracellular space:
• 80% as interstitial fluids
• 20% as plasma
*In infants and children, 70% of the body is water
Holliday MA, Segar WE Pediatrics (1957);19(5):823-32.
Water movement
• Water is not retained by any barrier within the
human body. It is free to flow between
compartments via passive or active means.
• Distribution between the compartments is
driven by:
– Hydrostatic pressure
– Osmotic gradients
– Oncotic gradients
Water balance
• Largely regulated by thirst and ADH release
• Over a 24 hour period the water balance is regulated
within 0.2%
– INs:
Tightly controlled between
285 and 295 mosm/L
• Water we drink (70-80%)
• Water in food (20-30%)
• Water produced endogenously
– OUTs:
• Kidneys: 1-2L of urine/day
• Skin: 450mL/ day (depends on the environment); up to 1-2L / hour
during heavy exercise
• Respiratory tract: 250-350mL/day
• GI tract: 200mL/day feces
Adapted from Knoers, N Engl J Med, 2005
2
11/5/2014
Intravenous fluids: a proven therapy
• Indications:
Intravenous fluids: the drug
• Indications:
1. Correct hypovolemia
2. Maintain hydration
1. Correct hypovolemia
2. Maintain hydration
3. Improve tissue oxygenation by augmenting
cardiac output through increased SV
From WAR “Fluid Resuscitation”
• In his 1923 landmark work, Walter Cannon summarized the
World War I experience and concluded that shock most
often resulted from intravascular volume deficits and must
be treated with restoration of blood volume to achieve
homeostasis (Cannon, 1923).
• Alfred Blalock, Professor of Surgery at the Johns Hopkins
University, extensively documented the importance of fluid
volume and its effect on survival and was one of the first to
note the importance of plasma in resuscitation.
– In more than 30 papers on shock published prior to World War
II, he provided extensive documentation that hypovolemia
(reduced blood volume in the body) was the most frequent
cause of death.
Types of fluids?
• Colloids (remain within the vascular
compartment)
– SyntheticHartmann’s
starches:Isotonic
hydroxyethyl
starch
4%
20%
Solutionsolutions
saline
albumin
Albumin
– Gelatin-based
Sodium
129
150
140
48-100
– Albumin
Chloride
109
150
128
19
Blood
135-145
95-105
• Crystalloids
(distribute
widely
across
body
fluid
Lactate
29
0
0
0
0
compartments)
– 1L 0.9NS approx 250mL will remain in the
intravascular compartment
– Isotonic saline vs. balanced solutions
Fluid Resuscitation: State of the Science for Treating Combat
Casualties and Civilian Injuries (1999)
Frank-Starling Curve
• CO = SV x HR
• Increased ventricular end-diastolic
volume by increasing preload will
increase SV
Ernest Henry Starling
(1866-1927)
3
11/5/2014
IVF: Side effects
Post-Vietnam era uncovered concerns regarding aggressive resuscitation:
•
– Tissue edema:
• Best detected in the lungs as fluids cross the alveolar-capillary interface causing a
condition coined as “Adult Respiratory Distress Syndrome”
– If given aggressive fluids during uncontrolled hemorrhage re-bleeding
– Given at room temperature (average 23oC) = negative thermal load, increased
metabolic demands on the body and overall hypothermia (which increases
bleeding)
– Hyperchloremic metabolic acidosis
Is this just an adult or
surgical problem?
Changes the composition of the blood detrimentally:
• Ringer’s lactate becomes crystalloid of choice for surgeons
–
• Coagulopathy
• Acidosis
– Fluid accumulation leads to compartment syndrome of the abdomen,
extremities, and pericardial effusions.
• Leads to MODS
FO is associated with worse outcomes
First Author
Surviving Sepsis campaign:
• Are there side effects?
Primary Results
Study design
Ref
Case series
Bone Marrow
Transplant (1994);
13:613-7.
Degree of FO at initiation much lower in survivors (16.4% vs 34%)
Retrospective chart review
Pediatrics (2001);
107(6): 1309-12
FO% was lower in survivors (7.8%) than in non-survivors (15.1%), FO
independently associated with survival in patients with MODS
Retrospective single center
chart review
CCM (2004); 32:17711776.
30 children after
BMT on RRT
FO>10% had decreased chance of renal recovery, 70% mortality in
this cohort
*Goldstein SL
21 children on
RRT
*Foland JA
113 PICU patients
on CRRT
Micheal M
26 BMT with AKI
All survivors had FO<10% using diuretics or CRRT, 9/15 non-survivors
Retrospective chart review
had FO
Pediatr Nephrol
(2004) 19;91-95
*Gillespie RS
Children on CRRT
FO>10% at CRRT initiation had a RR of 3.02 (95%CI 1.5,6.1) of
mortality
Pediatric Nephology
(2004); 16(12):13949.
*Goldstein SL
116 PICU patients
with MODS on
CRRT
Increased fluid administration from PICU admission to CRRT initiation Retrospective multi-center
is an independent risk factor for mortality
chart review
Kidney Int (2005);
67(2):653-8
Randolph AG
301 children on
CMV
Cumulative fluid balance did not predict prolonged weaning or
extubation failure
Prospective cohort
PCCM (2005) 6:642-7.
*Szekely A
411 children after Fluid intake in the first 24 hours was independently associated with
CPB
extended length of mechanical ventilation.
Prospective case series
Pediatric Anaesthesia
(2006); 16(11): 116675
*Shi S
172 neonates
after CPB
OR 10.06 for PMV in those with a positive post-operative fluid
balance.
Retrospective chart review
Chest(2008);
134(4):768-74.
*Hayes LW
77 PICU patients
on CRRT
FO>20% at CRRT start significantly associated with increased
mortality
Retrospective chart review
J Crit Care (2009);
24(3):394-400.
*Sutherland SM
297 PICU patients
on CRRT
FO>20% carried an OR of mortality of 8.5; 3% increase mortality for
every 1% increase FO
Prospective observational
multicenter trial
Am J Kid
Dis(2010):55(2):31625.
Algorithm for goal-directed management of hemodynamic support in children and
infants in septic shock.
Intravenous fluids: the drug
Study population
Lane PH
Retrospective single center
review
* Association between FO and outcomes is independent of patient acuity
Audience Participation: FO Math
FO =
(
)
x
()
100%
10kg child on maintenance IVF with normal UOP
INs= 40ml/hr x 4 days
Urine output = 1ml/kg/hr x 4 days.
Total balance = 3.84L-0.96L = +2.88L
% FO = 2.88L/10kg x 100% = 28.8%
4
11/5/2014
FO 10% = 100ml/kg
First Author
Study population
Primary Results
FO: chicken or egg
Study design
Ref
Lane PH
30 children after
BMT on RRT
FO>10% had decreased chance of renal recovery, 70% mortality in
this cohort
Case series
Bone Marrow
Transplant (1994);
13:613-7.
*Goldstein SL
21 children on
RRT
Degree of FO at initiation much lower in survivors (16.4% vs 34%)
Retrospective chart review
Pediatrics (2001);
107(6): 1309-12
*Foland JA
113 PICU patients
on CRRT
FO% was lower in survivors (7.8%) than in non-survivors (15.1%), FO
independently associated with survival in patients with MODS
Retrospective single center
chart review
CCM (2004); 32:17711776.
Micheal M
26 BMT with AKI
All survivors had FO<10% using diuretics or CRRT, 9/15 non-survivors
Retrospective chart review
had FO
Pediatr Nephrol
(2004) 19;91-95
*Gillespie RS
Children on CRRT
FO>10% at CRRT initiation had a RR of 3.02 (95%CI 1.5,6.1) of
mortality
Pediatric Nephology
(2004); 16(12):13949.
*Goldstein SL
116 PICU patients
with MODS on
CRRT
Increased fluid administration from PICU admission to CRRT initiation Retrospective multi-center
is an independent risk factor for mortality
chart review
Kidney Int (2005);
67(2):653-8
Randolph AG
301 children on
CMV
Cumulative fluid balance did not predict prolonged weaning or
extubation failure
Prospective cohort
PCCM (2005) 6:642-7.
*Szekely A
411 children after Fluid intake in the first 24 hours was independently associated with
CPB
extended length of mechanical ventilation.
Prospective case series
Pediatric Anaesthesia
(2006); 16(11): 116675
*Shi S
172 neonates
after CPB
OR 10.06 for PMV in those with a positive post-operative fluid
balance.
Retrospective chart review
Chest(2008);
134(4):768-74.
*Hayes LW
77 PICU patients
on CRRT
FO>20% at CRRT start significantly associated with increased
mortality
Retrospective chart review
J Crit Care (2009);
24(3):394-400.
*Sutherland SM
297 PICU patients
on CRRT
FO>20% carried an OR of mortality of 8.5; 3% increase mortality for
every 1% increase FO
Prospective observational
multicenter trial
Am J Kid
Dis(2010):55(2):31625.
Retrospective single center
review
SIRS, capillary leak AKI and MODS FO
– Worse SIRS = decreased
oxygen delivery and
tissue perfusion = AKI,
MODS and then FO
– SCr increases are
delayed by up to 2 days,
FO dilutes SCr and
delays AKI detection
further
• Unmasked AKI has worse
mortality
FO MODS
– ↓ decreasing perfusion
pressure to
encapsulated organs
– Cell separation =
abnormal cell-to-cell
interactions
– Dysfunctional ESL
– Abnormal O2 delivery
– ↓ lymphaƟc drainage
– Abdominal
compartment syndrome
* Association between FO and outcomes is independent of patient acuity
First Author
*Grist G
Study population
1540 children after CPB
Primary Results
Study design
Ref
Children with a positive fluid balance had an adjusted OR of
Retrospective chart review
1.73 for mortality
J Extracorp
Tech43(4):215-26.
*Selewski DT
53 children on ECMO and
CRRT
FO at CRRT start remained the most consistent predictor of
Retrospective chart review
mortality.
CCM (2012); 40:26942699.
*Arikan AA
80 children with respiratory
failure
Higher peak FO % predicted higher peak OI;
PCCM (2012);
13(3):253-8.
*Valentine S
*Askenazi DJ
*Hazle MA
*Willson DF
*Askenazi DJ
*Abulebda K
*Hassinger AB
*Sequin J
Retrospective chart review
24168
total
pediatric observational
studies
thatto VFD,
report
BAL on d3 was inversely
proportional
childrenfluid
are overload or
children with ARDS
Multicenter cohort
managed with more than “liberal” fluids
a positive fluid balance
is associated with worse outcomes and/or
survival, children able to return to dry weight during
mortality in patients 43%
(total
n=4,124):
CRRT were more likely to survive than children who
Prospective cohort analysis
84 children on CRRT
of the ppCRRT registry
FO (78% vs 35%); FO<10% versus >20% had a
1. on CRRTremained
(n=668)
adjusted OR 4.8 (1.3,17.7)
2. after CPBEarly
(n=2093)
post-operative fluid overload was associated with
49 neonates <6mo
Prospective observational
need
for RRT, extended LMV and LOS and increased
3.
on
ECMO
(n=53)
undergoing CPB
study
mortality.
4. with respiratory failure (n=381)
Secondary analysis of
PICU MDs follow a liberal fluid management approach in
CALFACTANT (in which there
5. with
(n=277)
109 children with
ARDS ARDS
ARDS,
positive fluid balance associated with higher OI,
was a strict fluid
LMV,
and increased mortality.
6. Neonates
(n=279)
management protocol)
Weight
accumulation
at DOL#3 was significantly associated Prospective observational
7. with septic
shock
(n=317)
58 neonates, >34 wks GA
with AKI and with mortality.
trial
8. after bone marrow transplant (n=56).
CCM (2012);40:28832889
J Pediatr
(2013);162:587-592.e3
PCCM (2013);14:44-49.
PCCM (2013); 14:66672.
Pediatric Nephrol
(2013); 28(4):661-6.
317 children with septic
shock
FO = increased OR for mortality for those patients in the
low-risk sepsis cohort but not in the medium or high-risk
sepsis cohorts
Retrospective analysis of a
multicenter sepsis database
CCM (2014) 42(2):397403.
98 children after CPB
5% FO associated with 2 days longer in the ICU and on
mechanical ventilation; FO preceded AKI.
Retrospective analysis of a
prospective observational
study
PCCM(2014);
15(2):130-8.
193 children after CPB
FO at post-operative day #2 predicted extended length of
stay and length of mechanical ventilation. Worse daily % of
FO predicted worse OI.
Retrospective cohort study
CCM(2014); S15300293 (ePub ahead of
print).
To prove causality:
Persistent association in different conditions
Dose-dependent response
Timing
Biologic plausibility that FO would cause
worse outcomes
Does prevention of FO improve outcomes?
* Association between FO and outcomes is independent of patient acuity
Question of the hour?
1. Is this a necessary risk?
Isn’t capillary leak just a symptom of severity?
Children with FO are sicker and therefore have
worse outcomes…
Fluid
Sicker
patient
Overload
MODS and
death
5
11/5/2014
To prove causality:
Persistent association in different conditions
Dose-dependent response
Timing
Biologic plausibility that FO would cause
worse outcomes
Does prevention of FO improve outcomes?
To prove causality:
Persistent association in different conditions
Dose-dependent response
Timing
Biologic plausibility that FO would cause
worse outcomes
Does prevention of FO improve outcomes?
Starling’s Original Principle
Does FO precede MODS?
1
2
1
2
3
Jacob M Curr Opin Crit Care 2013;19:282-9.
Modern updates:
1. Force limiting pressure-dependent fluid filtration is independent of the
interstitial protein concentration
2. Intravascular presence of low albumin concentration does not add another
force to the system but increases the “hydraulic conductivity” across the ESL
3. Fluid is not resorbed on the venous side, excesses are returned exclusively via
the lymphatics.
AKI occurs
pRIFLE “F”
Interstitial edema is avoided
• Intact barrier
• Normal hydrostatic pressures
• No change in the coefficient, Kf
6
11/5/2014
Loss of an intact barrier
• Excessive production of matrix
metalloproteinase 9 (MMP-9) is linked to
tissue damage and anastomotic leakage after
large bowel surgery
• Intravascular hypervolemia = release of ANP
which induces matrix metalloproteases to
digest the endothelial glycocalyx within 1 hr
Cytokines during SIRS =
lost VE-cadherin
EDEMA
Volta CA Anesthesiology 2007;106:85-91.
Endothelial surface layer (ESL)
•
•
•
Glycocalyx bound to plasma constituents, primarily albumin*
Under healthy conditions, the ESL resists fluid and solute filtration into the
interstitium
Glycocalyx is disrupted by inflammatory mediators in sepsis,
ischemia/reperfusion, diabetes, trauma, resuscitation, and arteriosclerosis
– Hypervolemia endangers vascular barrier competence.
– Inflammatory degradation of the ESL increases vascular permeability with
transcapillary escape of albumin.
•
Hypervolemia on the ESL
Use of crystalloids without measurement of volume responsiveness with
result in accumulation in connective tissues
*Plasma albumin
concentrations ¼ of the
normal appear to be
enough to maintain an
intact glycocalyx
HypervolemiaMODS
Interstitial edema reduces the efficacy of gas
exchange at alveolar and tissue levels
• Compromises oxygen delivery from the outside world
to the mitochondria at 2 crucial sites:
1. Across the alveolar-arterial membrane where diffusion of gas
is dependent on thickness of this membrane
2. In the tissues where oxygen extraction from capillaries and
CO2 clearance are impaired
*Ospina-Tascon G ICM 2010;36:945-955.
Hypervolemia and the ESL
• Colloid induced
hypervolemia =
– 60% loaded in the
interstitial
compartment as
edema
– Reduced ESL volume
to 1/3 of the original
value
Adequate
Critical
Anoxic
Rehm M Anestheiology2001;95:849-856.
7
11/5/2014
To prove causality:
FACCT Results
Persistent association in different conditions
Dose-dependent response
Timing
Biologic plausibility that FO would cause
worse outcomes
Does prevention of FO improve outcomes?
If FO is prevented, do outcomes
change?
Pediatric RCTs of fluid management
SIRS
Capillary
leak
Edema
Fluid
resuscitation
• Randomly assigned children with severe
febrile illness and impaired perfusion to
receive boluses of either 20ml/kg, 40ml/kg or
none at time of hospital admission.
8
11/5/2014
NEJM (2011); 364(26):2483-95.
FEAST trial
• Mechanisms by which bolus-fluid
administration had adverse biologic effects:
– Interruptions of catecholamine-mediated hostdefense respones by rapidly increasing plasma
volume
– Reperfusion injury by rapidly increasing plasma
volume
– Transient hypervolemia = exacerbated capillary
leak leading to ICH and pulmonary edema
Is FO preventable?
9
11/5/2014
FO: Conclusions based on the data to
date
Raghunathan et al.
Curr Opin Crit Care
2013; 19(4):290-8.
3 Phases of Sepsis
Surviving Sepsis campaign, algorithm.
The phases of FO in critical illness
When does
this transition
occur?
EGTD
decrease inflammation,
improve mortality
Restrictive fluid management
Decreases ALI/ARDS
Decreases AKI
Decreases LOS, LMV, mortality
10
11/5/2014
r=0.27, r2=0.01
Conclusions
• Intravenous fluids are a drug with an appropriate dose,
indication and potential for adverse effects.
• Fluid overload is independently associated with worse
outcomes in children.
• Fluid overload may cause worse outcomes in children.
• Fluid overload could be preventable.
• Thoughtful resuscitation (not to just CVP!) and use of
inotropes and vasopressors is essential early.
• Restrictive fluid management to avoid fluid overload
after stabilization is likely to be life saving.
Fluid resuscitation targets
• When using BP or urine output to guide fluid
management, large doses of fluids result and
are harmful.
• CVP guided management alone is harmful*
• Better targets exist such as pulse pressure
variation and variations in sonographic
dimensions
– Pulse pressure variation: AUC 0.94
– Stroke volume variaUon: AUC 0.84†
Fluid overload: are we drowning
our patients?
Amanda Hassinger, MD
Attending Physician, Pediatric Critical Care
Pediatric Grand Rounds
November 7, 2014
*Boyd JH. CCM (2011); 39:259-265.
†Marik PE. CCM (2009); 37:2642-2647.
11